Disease relevance of ZNF384

• These results also extend the involvement of TET-protein fusions to acute lymphoblastic leukemia and suggest a role for CIZ/NMP4 in lymphoid and myeloid development [1].
• Huntington's disease is a progressive autosomal dominant neurodegenerative disorder caused by expansion of a CAG repeat coding for polyglutamine in the huntingtin protein [2].
• To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients [3].
• Of 1007 patients with signs and symptoms compatible with a diagnosis of Huntington's disease, 995 had an expanded CAG repeat that included from 36 to 121 repeats (median, 44) (sensitivity, 98.8 percent; 95 percent confidence interval, 97.7 to 99.4 percent) [4].
• In addition, the length of the CAG repeat was determined in 113 control subjects with a family history of Alzheimer's disease (44 patients), schizophrenia (39), major depression (16), senile chorea (5), benign hereditary chorea (5), neuroacanthocytosis (2), and dentatorubropallidoluysian atrophy (2) [4].

Psychiatry related information on ZNF384

• BACKGROUND: The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat [5].
• The age of the patient at disease onset was not lower than those of heterozygotes with the same CAG-repeat sizes, but the clinical manifestations were rapidly progressive dementia and chorea [6].
• Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder [7].
• Analysis of CAG repeat expansions in restless legs syndrome [8].
• Physical and mental health were documented using the Medical Outcomes Study 36-Item Short-Form Health Survey. Subgroup analyses assessed the influence of age, sex, age at onset, duration of the disease, phenotype, and CAG repeat length on test performance [9].

High impact information on ZNF384

• Spinocerebellar ataxia type 1 (SCA1) is one of several neurological disorders caused by a CAG repeat expansion [10].
• The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases [11].
• By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients [12].
• Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion that lengthens a glutamine segment in the novel huntingtin protein [13].
• These mice develop a phenotype similar to the human translated CAG repeat disorders [14].

Chemical compound and disease context of ZNF384

• Huntington's disease (HD) results from the expansion of a polyglutamine encoding CAG repeat in a gene of unknown function [15].
• Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level [16].
• To determine that reason, we analyzed a panel of lung cancer cell lines, using HpaII or HhaI restriction enzymes, methylation-specific PCR, and bisulfite genomic sequencing of the polymorphic CAG repeat site of AR exon 1, including nearby CpG sites [17].
• We conclude that a low number of CAG repeat in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are both important risk factors for coronary heart disease [18].
• Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length [19].

Biological context of ZNF384

• Transcription factor ZNF384/CIZ/NMP4 was first cloned in rat as a p130Cas-binding protein and has a role in bone metabolism and spermatogenesis [20].
• We show here that E2A-CIZ also transforms 3T3 fibroblasts, suggesting that the addition of a transactivation domain to the CIZ protein is involved in this phenotype [21].
• Fusion of a transactivation domain to CIZ is suggestive for a transactivating function in transformation [21].
• Deletion of the zinc fingers of CIZ resulted in loss of both DNA-binding and transforming properties of TAF15-CIZ, whereas deletion of the other functional domains of CIZ had no effect [21].
• Some of these isoforms recently have been identified as Cas-interacting zinc finger proteins (CIZ) that localize to fibroblast focal adhesions and enhance metalloproteinase gene expression [22].

Anatomical context of ZNF384

• Cellular transformation of NIH3T3 fibroblasts by CIZ/NMP4 fusions [21].
• CONCLUSION: These data suggest that the binding of p130(cas) and NMP-4 to the AGRE site regulates MMP-13 expression and may trigger the change in human chondrocytes from the L-OA state to the H-OA state [23].
• We previously indicated that nuclear matrix proteins (NP/NMP4) interact with the rat type I collagen alpha1(I) polypeptide chain (COL1A1) promoter at two poly(dT) sequences (sites A and B) and bend the DNA [22].
• We conclude that NP/NMP4/CIZ is a novel family of nuclear matrix transcription factors that may be part of a general mechanical pathway that couples cell structure and function during extracellular matrix remodeling [22].
• We observed NP/NMP4/CIZ expression in osteocytes, osteoblasts, and chondrocytes in rat bone [22].

Associations of ZNF384 with chemical compounds

• The CAG repeat, coding for a polyglutamine tract, lies within the coding region [24].
• The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms [3].
• AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes [25].
• The CAG repeat, which is expanded in DRPLA, is located 1,462 bp downstream from the putative methionine initiation codon and encodes a poly-glutamine tract [26].
• Although poly-serine and proline tracts exist near the CAG repeats, these polyserine or proline tracts did not show any polymorphisms, which is in strong contrast to the high heterogeneity in the length of the CAG repeat [26].

Physical interactions of ZNF384

• Furthermore, MSH2 bound preferentially to looped-out CAG repeat sequences, implicating a strand asymmetry in MSH2 recognition [27].
• Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17 [28].

Regulatory relationships of ZNF384

• RESULT(S):A new 173A-->T (Q58L) substitution at the beginning of the CAG repeat in the transactivation-regulating domain of the androgen receptor was found in 2 infertile Finnish men but not in 60 other infertile men or 60 controls [29].
• Comparison between the CAG repeat length distribution of control and Parkinson's disease samples revealed no evidence of either germ line or somatic POLG CAG repeat instability in Parkinson's disease patients [30].
• A familial factor independent of CAG repeat length influences age at onset of Machado-Joseph disease [31].
• Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript [32].
• The CAG repeat expansion is very likely translated and expressed as indicated by the detection of a polyglutamine-containing protein in an ADPSP patient [33].

Other interactions of ZNF384

• Given the interaction between human zyxin and p130CAS, these results suggest that zyxin indirectly enables the interaction of ZNF384 with p130CAS which is described in rat [20].
• Molecular cloning of the translocations t(12;22)(p13;q12) and t(12;17)(p13;q11) in acute leukaemia showed that either EWSR1 or its homologue TAF15 are fused to the transcription factor CIZ [21].
• Luciferase experiments indeed showed that E2A-CIZ as well as VP16-CIZ transactivates the MMP7 promoter [21].
• In addition, a new fusion E2A-CIZ was recently cloned as a result of a t(12;19)(p13;p13) in a patient with acute lymphoblastic leukaemia [21].
• Supershift experiments showed the presence of p130cas and nuclear matrix transcription factor 4 (NMP-4) in the wild-type AGRE/H-OA chondrocyte complex [23].

Analytical, diagnostic and therapeutic context of ZNF384

• Sequence analysis provides strong evidence that the first in frame methionine 5' to the CAG repeat, is the translational start site, for both the mouse and human transcript [34].
• In order to better understand the role of nuclear localization of polyglutamine in the human CAG repeat disorders, gene targeting was used to add either nuclear localization (NLS) or nuclear export (NES) signals to versions of the mouse Hprt protein containing expanded polyglutamine (HprtQ150) [35].
• Recently, part of the gene responsible for this disorder was cloned containing a CAG repeat, and predominant neuronal expression of the gene was proved only through Northern blot analysis in rats [36].
• Eleven p-HD subjects (age, 45.8 +/- 11.0 years; CAG repeat length, 41.6 +/- 1.8) and 11 age-matched control subjects (age, 45.3 +/- 13.4 years) underwent H(2) (15)O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks [37].
• Chromatin immunoprecipitation of epitope-tagged Hmo1 selectively precipitates CAG repeat tracts DNAs that range from 26 to 126 repeat units [38].

References